A universal malaria T cell vaccine based on HLA-E presentation

Active Project Grant Awarded Last action

Award ID
R01AI168092
Recipient
Awarding agency
Obligated
$5,109,815

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 90% complete
Place of performance
Portland, OR 97239, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Malaria-specific CD8+ T cells have long been known to control the liver stages of malaria. We recently showed that they can also kill reticulocytes infected with plasmodium vivax. However, the T cell targeted antigens presented by major histocompatibility complex (MHC) class I molecules on parasite-infected cells at any stage are largely unknown; a lack of knowledge that has hampered the development of rationally designed, T cell- based vaccines for malaria. In preliminary experiments we determined the MHC-I peptidome presented on P. Vivax-infected reticulocytes. This analysis revealed that many MHC-I-bound peptides are derived from abundant house-keeping proteins such as histones and ribosomal proteins that are highly conserved among plasmodium species-targets not represented in current vaccine strategies. This discovery thus creates the unique opportunity to develop pan-plasmodium vaccines eliciting T cells to validated targets. Unexpectedly, several peptides were identified in multiple donors regardless of their MHC-haplotype and our preliminary data show this is in part due to peptide presentation on MHC-E, a non-polymorphic MHC-IB molecule. We therefore hypothesize that MHC-E-restricted CD8+ T cells contribute to T cell-mediated protection against malaria and that this can be exploited for vaccine design using cytomegalovirus (CMV)-based vectors, the only platform that can be programmed to elicit MHC-E-restricted CD8+ T cell responses to inserted antigens. This hypothesis will be tested in three specific aims using the P. Cynomolgi non-human primate model of P. Vivax with validation in human P. Vivax-infected samples: in aim 1 we will determine the relative contribution of MHC-E to presentation of P.vivax peptides to CD8+ T cells and investigate a possible role of MHC-E-targeting in CD8+ T cell killing of infected reticulocytes (IRETICS). In aim 2 we will characterize the role of individual P. Vivax antigens in MHC-E-restricted CD8+ T cell targeting of IRETICS. This will be accomplished by identifying MHC- E/peptide-specific T cell receptors and examining the ability of TCR-transfected T cells to target IRETICS . In addition, we will similarly characterize MHC-E-restricted CD8+ T cells elicited to selected antigens in rhesus macaques immunized with genetically modified rhesus cytomegalovirus vectors (RHCMV) that elicit exclusively MHC-E-restricted CD8+ T cells. In aim 3, we will compare RHCMV-based P. Vivax vaccines eliciting MHC-E or MHC-IA-restricted responses to selected, conserved antigens with respect to their ability to protect against P. Cynomolgi challenge in rhesus macaques. Specifically, we will monitor protection against the liver stage, primary blood stage and relapsing blood stage resulting from dormant liver stages. This collaborative program brings together diverse expertise and, if successful, will provide a highly innovative approach to malaria vaccine development that is expected to have a lasting impact on vaccine research.

Transactions

Action Obligated Date
Amendment $717,810
Amendment $706,784
Amendment $705,028
Amendment $705,028
Amendment $0
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Amendment $0
Amendment $771,027
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Amendment $752,069
Original award $752,069
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Subawards

Subrecipient Amount Awarded
Fondazione Per L'istituto DI Ricerca In Biomedicina (Irb) A universal malaria T cell vaccine based on HLA-E presentation $788,810

Quick answers

Who received award R01AI168092?

R01AI168092 was awarded to Oregon Health & Science University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 20, 2022.

How much is award R01AI168092 worth?

$5,109,815 has been obligated on R01AI168092.

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